APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

Description A rare APOE variant APOE3-Jac reduces self-aggregation and promotes healthy brain aging. Targeting APOE aggregation Genetic variants in the APOE gene have been shown to modulate the risk of developing Alzheimer’s disease (AD). The APOE3-V236E variant, called APOE3-Jacksonville (APOE3-Jac), has been shown to reduce the risk of AD. Now, Liu et al. investigated the mechanisms mediating the protective effects of APOE3-Jac. The protective variant was found to reduce apoE aggregation, leading to increased lipid association. APOE3-Jac expression in a mouse model of AD reduced brain pathology and, when introduced in APOE4, the variant reduced its aggregation in vitro. The results suggest that targeting APOE aggregation might be effective in reducing disease pathology associated with AD. Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.

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